This invention relates to the field of organometallic chemistry. In particular, this invention relates to methods for the preparation of organometallic complexes useful as reactive intermediates in organic synthesis, especially for the formation of carbon-to-carbon bonds.
The utility of organocopper complexes as reactive intermediates in a variety of synthetic reactions has been well known for decades. Particularly important reactions utilizing organocopper complexes in the formation of carbon-to-carbon bonds include addition reactions (such as 1,4-conjugate additions and carbocupration reactions) and substitution reactions (such as, for example, the displacement of halides, tosylates or mesylates and ring opening of epoxides). In such reactions, the organocopper complex formally serves as the source of a suitable carbanion for introduction into a target molecule by addition or displacement.
Early work in the field of organocopper chemistry involved treatment of either catalytic or stoichiometric quantities of a copper(I) halide with a Grignard (RMgX) or organolithium (RLi) reagent. The resultant products are either neutral organocopper reagents RCu(I) or copper(I) monoanionic salts R.sub.2 CuM (M =Li or MgX), commonly referred to as lower order or Gilman reagents. Copper(I) cyanide is also an excellent precursor for the direct formation of lower order cyanocuprates RCu(CN)Li upon treatment with an equivalent of an organolithium. It is believed that the strength of the Cu-CN linkage accounts for the direct cuprate formation with one equivalent of the organolithium, rather than the metathesis that occurs with copper(I) halides to produce an equivalent of LiX.
While such lower order complexes have some direct synthetic applications, it has further been determined that reagents of this type can be composed of different ligands (i.e., R.noteq.R'). In other words, rather than forming a complex of the formula R.sub.2 CuLi from two equivalents of the same RLi, different organolithium compounds can be used to provide a complex of the formula R.sub.T R.sub.R CuLi. In this manner, it is possible to conserve potentially valuable R.sub.T Li. Successful exploitation of such complexes comprising two different ligands is based on the ability to control the selectivity of transfer of the desired ligand R.sub.T rather than the residual (or "dummy") group R.sub.R from copper to electrophilic carbon.
A particularly significant advance in the field of organocopper complexes has been the development of so-called "higher order" cuprates For example, the admixture of two equivalents of RLi (or one equivalent each of R.sub.T Li and R.sub.R Li) with copper(I) cyanide proceeds to the formation of a copper(I) dianionic complex or higher order cyanocuprate, R.sub.2 Cu(CN)Liz The cyano ligand, with its .pi.-acidic nature, is believed to enable the copper to accept a third negatively-charged ligand in ethereal solvents (e.g., Et.sub.2 O and THF). Such higher order complexes, particularly those derived from two different organolithium compounds, have been successfully exploited as highly selective and efficient means of making key carbon-to-carbon bonds.
The use of cuprates in 1,4-conjugate addition reactions for introduction of unsaturated carbanions is especially attractive due to the complete control of double bond geometry in the reaction scheme. This is of particular significance, for example, in the synthesis of various prostaglandins via conjugate addition of an alkenyl moiety to the unsaturated ketone functionality of a substituted cyclopentenone.
To date, the preparation of reactive vinylic organocuprate reagents has involved a limited number of typical reaction pathways In particular, for transfer of a particular alkenyl side chain to a target molecule, either a vinylic halide (usually, the bromide or iodide) or a vinylic stannane has usually been employed as a precursor molecule. These precursor molecules are generally prepared from a corresponding acetylene and converted to the reactive copper reagents for use as synthetic intermediates.
U.S. Pat. No. 4,777,275 to Campbell et al., the disclosure of which is hereby incorporated by reference, describes a process for preparing a higher order copper complex in which a ligand (designated R.sub.t) which is desired in a subsequent synthetic organic reaction to form a new carbon-to-carbon bond is transferred in situ from a stannane compound to a first higher order copper complex to form a second higher order copper complex including the ligand. Of course, to employ this method it is first necessary to prepare specific vinyl stannanes by art recognized techniques. Such techniques generally call for the reaction of a suitable acetylene with, e.g., a trialkyl tin hydride. Unfortunately, the stannanes are generally quite toxic. Therefore, it would be advantageous to avoid such intermediates entirely if possible.
Preparation of suitable cuprate complexes from the corresponding halides is also problematic, particularly in the case of alkenylhalides. Formation of the desired cuprates is generally effected from the corresponding alkenyllithium compounds, which in turn are prepared by metal-halogen exchange (typically using two equivalents of highly pyrophoric and expensive t-butyllithium) with the corresponding alkenylhalides or reaction of the halides with lithium metal. Preparation of the organolithium precursors via this latter method is typically tedious, and may result in low yields. Moreover, in the case of the alkenyl compounds, there may be some loss of double-bond stereochemistry.
According to U.S. Pat. No. 4,415,501 to Grudzinskas et al., the disclosure of which is also hereby incorporated by reference, some of the potentially problematic issues associated with the chemistry involved in the formation of vinylic cuprate complexes are avoided by utilizing an alternative class of reagents. A class of alkenylzirconium reagents are described, which may be employed directly in various conjugate addition reactions. These alkenylzirconium reagents are prepared by reaction of the corresponding protected alkynol with dicyclopentadienyl zirconium chlorohydride; the latter is typically generated in situ by the reduction of dicyclopentadienyl zirconium dichloride in solution under an inert atmosphere. The thus-prepared alkenylzirconium reagents are described as moisture sensitive, and thus it is suggested that they are best prepared just prior to use. Reaction of the alkenylzirconium reagents with the target molecule for a conjugate addition is effected in the presence of a catalytic amount of a reduced nickel catalyst.
While the method of U.S. Pat. No. 4,415,501 obviates some of the potential problems associated with the formation of the reactive cuprates, it does so at the cost of yield and purity of the resultant products, as is immediately apparent from a review of Table II of the reference. Indeed, while the products of hydrozirconation reactions may be utilized in selected coupling reactions to form carbon-to-carbon bonds, there is no general established method for directly transferring these ligands to alpha, beta unsaturated ketones in a conjugate (i.e., 1,4-) sense. Therefore, the reference method using organozirconium compounds directly as reagents is limited in applicability and clearly unacceptable for the preparation of most products, in particular from relatively expensive optically-active intermediates, on a commercial scale.
It is an object of the present invention to provide a method for the preparation of suitable organometallic intermediates for use in the transfer of a particular carbanion equivalent (e.g., a vinylic organometallic species) to a target molecule with the formation of carbon-to-carbon bonds pursuant to the heretofore known reaction mechanisms involving such carbanions.
In particular, it is an object of the present invention to provide a method for the preparation of reactive organometallic intermediates which results in a high yield of both the intermediates and of the final products prepared via such intermediates.
In addition, it is a further object of the present invention to provide a method for the preparation of reactive organometallic intermediates for use in the preparation of a variety of products exploiting known reaction mechanisms formally involving carbanions (such as 1,4-conjugate additions or displacement reactions) without the need to prepare or isolate halide or stannane precursors of the subject organometallics.